Protease inhibitors inhibit proteases, which are proteins responsible for hydrolyzing peptides or proteins into their carboxylic acid and amine components. Protease inhibitors have been used to prevent or treat viral infections, including HIV and Hepatitis C, both of which require protease activity for the infection process. In the case of HIV, protease inhibitors prevent replication by inhibiting the activity of HIV-1 protease, a viral enzyme that cleaves nascent proteins for final assembly of new virions.
Protease inhibitors have been developed or are presently undergoing testing for treating various viral infections, such as HIV infections. Examples of anti-HIV protease inhibitors are saquinavir (Fortovase™, Invirase™, Hoffman-La Roche), ritonavir (Norvir™, Abbott), indinavir (Crixivan™, Merck), nelfinavir (Viracept™, Agouron), amprenavir (Agenerase™, GlaxoSmithKline), lopinavir (Kaletra™, Abbott), atazanavir (Reyataz™, Bristol-Myers Squibb), fosamprenavir (Lexiva™, Telzir™, GlaxoSmithKline), tipranavir (Aptivus™, Boehringer-Ingelheim) and darunavir (Prezista™, Tibotec). Examples of protease inhibitors experimentally used for hepatitis C treatment are BILN 2061 (Bohringer Ingleheim), VX 950 (Telaprevir™, Vertex and Johnson & Johnson), and SCH 503034 (Schering-Plough).
Researchers are further investigating the use of anti-HIV protease inhibitors as anti-protozoals for use against malaria and gastrointestinal protozoal infections. A combination of ritonavir and lopinavir was found to have some effectiveness against Giardia infection (Dunn et al., 2007, Int. J. Antimicrob. Agents 29(1): 98-102). The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties (Andrews et al., 2006, Antimicrob. Agents Chemother. 50(2):639-48). A cysteine protease inhibitor drug was found to cure Chagas's disease in mice (Doyle et al., 207, Antimicrob. Agents Chemother. 51(11):3932).
Protease inhibitors have been further evaluated in the treatment of cancer. For example, nelfinavir and atazanavir are able to kill tumor cells in culture (Gills et al., 2007, Clin. Cancer Res. 13(17):5183-94; Pyrko et al., Cancer Res. 67(22):10920-28). Proteasome inhibitors, such as Velcade™, are now front-line drugs for the treatment of various cancers, notably multiple myeloma.
Due to the great interest in protease inhibitors, effort has been devoted to the design and synthesis of novel scaffolds that combine protease inhibition capability and good developability properties. One such novel class of compounds is the silanediol-based dipeptide analogs, such as (1). The structure of (1) mimics the structure of the hydrated carbonyl compound (2), which is an intermediate of the hydrolysis reaction of a peptide to the carboxylic acid fragment (3) and amine fragment (4). As a structural mimic of (2), compound (1) binds to the protease active site and inhibits its activity.

Compounds such as (1) have been prepared by a process involving approximately 15 steps, which is far too long a synthetic route to be practical. The final step of the synthesis is treatment of diphenylsilane (5) with acid, whereby a silanediol (1) is formed. Compound (5) could in principle be prepared by a condensation reaction analogous to the addition of a silyl anion (8) to a sulfinimine (7) (Nielsen & Skrydstrup, 2008, J. Am. Chem. Soc. 130:13145-51). Silyl anion (8) may be formed by treating a chlorosilane (9) with lithium metal or a lithium salt. Chlorosilanes are cheap and readily available but are extremely moisture sensitive and fume when exposed to air. Less commonly, a proteosilane (10) is used as a precursor to (8). Proteosilane (10) is easier to manipulate but is generally prepared from a moisture-sensitive chlorosilane.

Due to the strength of the Si—O bond in a siloxy compound, its conversion to a silyl metal derivative is largely unexplored in the chemical literature. An early report described the conversion of triphenylsiloxyethane to triphenylsilyl sodium using sodium-potassium alloy in 40% yield (Benkeser et al., 1952, J. Am. Chem. Soc. 74:648-50). This report did not use substrates containing fewer than three phenyl groups attached to the silicon atom. A more recent report described the conversion of 1-dimethylphenylsiloxydecane to 1-decanol via treatment with lithium naphthalide, followed by acidic hydrolysis (Alonso et al., 1997, Tetrahedron 53:14355-68). This report did not describe the fate of the silicon group, and the synthetic protocol was rather cumbersome and difficult to scale up (Behloul et al., 2005, Tetrahedron 61:6908-15).
There is thus a need for the development of a novel synthetic methodology that allows for the efficient and convenient synthesis of a silanediol-based dipeptide analog such as (1). The synthetic methodology should allow for the synthesis of targeted compounds from commercially available and inexpensive compounds that are easy to handle. The present invention addresses and meets these needs.